Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats.
Bisphenol A (BPA) is an estrogen-mimicking endocrine disruptor. Early-life exposures to low doses of BPA exert long-lasting effects on animals' reproductive and brain physiology. However, little is known about the effects of BPA on the stress-response system. Given the interaction of sex and stress hormones, we examined the effect of a low perinatal BPA exposure on the function of the hypothalamic-pituitary-adrenal (HPA) axis at rest and upon application of acute stress. Throughout pregnancy and lactation rats received daily 40 μg BPA/kg body weight orally via cornflakes. We studied the effect of this low but chronic exposure to BPA in the male and female offspring at puberty. BPA exposure led to abnormal adrenal histology including reduced zona reticularis especially in male offspring, hyperplasia of zona fasciculata in both sexes, and increased adrenal weight in female offspring. BPA-treated females had increased basal corticosterone and reduced hypothalamic glucocorticoid receptors (GR) levels. Stressed BPA-exposed females exhibited anxiety-like behavioral coping, a less rigorous corticosterone response, and did not downregulate GR in the hypothalamus, compared with control females. BPA-exposed males exhibited a heightened corticosterone stress response compared with females; they also displayed increased pro-opiomelanocortin mRNA levels and retained the prestress levels of pituitary corticotropin-releasing hormone-receptor 1, compared with control males. We found that perinatal chronic exposure to a low dose of BPA perturbs the basal and stress-induced activity of the HPA axis in a sexually dimorphic manner at adolescence. Exposure to BPA might contribute to increased susceptibility to stress-related disorders in later life.


Total observed caries experience: assessing the effectiveness of community-based caries prevention.
To compare common measures for dental caries in longitudinal caries research in support of a new measure, the Total Observed Caries Experience (TOCE). TOCE was calculated as the total number of decayed or filled teeth ever observed. TOCE was compared to dmft, DMFT, and the prevalence of untreated decay using data from a 4-year, cluster randomized community-based caries prevention program. Outcomes were analyzed using generalized estimating equations and assessed change over time and effects across treatment groups. For TOCE and DMFT, the risk of caries over time increased. In contrast, risks decreased for dmft and the prevalence of untreated decay, driven largely by decayed primary teeth being exfoliated. Effects across treatment groups showed increased risk for some outcomes and attenuated risks in others; however, treatment effects for TOCE were more in line with expected results when compared with controls. TOCE accounts for caries on primary and permanent dentition and is not subject to bias due to exfoliation. It can be used as a robust measure to evaluate community-based caries prevention programs.


Source coherence impairments in a direct detection direct sequence optical code-division multiple-access system.
We demonstrate that direct sequence optical code- division multiple-access (DS-OCDMA) encoders and decoders using sampled fiber Bragg gratings (S-FBGs) behave as multipath interferometers. In that case, chip pulses of the prime sequence codes generated by spreading in time-coherent data pulses can result from multiple reflections in the interferometers that can superimpose within a chip time duration. We show that the autocorrelation function has to be considered as the sum of complex amplitudes of the combined chip as the laser source coherence time is much greater than the integration time of the photodetector. To reduce the sensitivity of the DS-OCDMA system to the coherence time of the laser source, we analyze the use of sparse and nonperiodic quadratic congruence and extended quadratic congruence codes.


Dynamic causal models of neural system dynamics:current state and future extensions.
Complex processes resulting from interaction of multiple elements can rarely be understood by analytical scientific approaches alone; additional, mathematical models of system dynamics are required. This insight, which disciplines like physics have embraced for a long time already, is gradually gaining importance in the study of cognitive processes by functional neuroimaging. In this field, causal mechanisms in neural systems are described in terms of effective connectivity. Recently, dynamic causal modelling (DCM) was introduced as a generic method to estimate effective connectivity from neuroimaging data in a Bayesian fashion. One of the key advantages of DCM over previous methods is that it distinguishes between neural state equations and modality-specific forward models that translate neural activity into a measured signal. Another strength is its natural relation to Bayesian model selection (BMS) procedures. In this article, we review the conceptual and mathematical basis of DCM and its implementation for functional magnetic resonance imaging data and event-related potentials. After introducing the application of BMS in the context of DCM, we conclude with an outlook to future extensions of DCM. These extensions are guided by the long-term goal of using dynamic system models for pharmacological and clinical applications, particularly with regard to synaptic plasticity.


Surgical site infection in the elderly following orthopaedic surgery. Risk factors and outcomes.
Risk factor and outcomes data pertaining to surgical site infection in the elderly following orthopaedic operations are lacking. The aim of this study was to identify risk factors for surgical site infections and to quantify the impact of these infections on health outcomes in elderly patients following orthopaedic surgery. A risk factor and outcomes study was performed at Duke University Medical Center, a tertiary care center, and seven community hospitals in North Carolina and Virginia between 1991 and 2002. The study included elderly patients in whom a surgical site infection had developed following orthopaedic surgery and elderly patients in whom a surgical site infection had not developed following orthopaedic surgery (controls). Outcome measures included mortality during the one-year postoperative period and the total length of the hospital stay (including readmissions during the ninety-day postoperative period). One hundred and sixty-nine patients with a surgical site infection were identified, and 171 controls were selected. The mean age of the patients was 74.7 years. The most frequent procedures were hip arthroplasty (n = 74, 22%) and open reduction of fractures (n = 55, 16%). The most common pathogen was Staphylococcus aureus (n = 95, 56%). A risk factor for surgical site infection, identified in the multivariate analysis, was admission from a health-care facility (odds ratio = 4.35; 95% confidence interval = 1.64, 11.11). Multivariate analysis also indicated that surgical site infection was a strong predictor of mortality (odds ratio = 3.80; 95% confidence interval = 1.49, 9.70) and an increased length of stay in the hospital (multiplicative effect = 2.49; 95% confidence interval = 2.10, 2.94; 9.31 mean attributable days per infection, 95% confidence interval = 6.88, 12.13). Measures for prevention of surgical site infection in elderly patients should target individuals who reside in health-care facilities prior to surgery. Future studies should be done to examine the effectiveness of such interventions in preventing infection and improving outcomes in elderly patients who undergo orthopaedic surgery.


Outcome of newborns with asymptomatic monomorphic ventricular arrhythmia.
Frequent premature ventricular contractions (PVCs), couplets (CPLTs) and episodes of ventricular tachycardia are extremely rare in the neonatal population. Limited information is available with regard to clinical relevance and outcome. To evaluate the clinical characteristics and outcomes of a group of newborns with ventricular arrhythmias without heart disease. Between January 2000 and January 2003, 16 newborns with ventricular arrhythmias in the absence of heart disease were studied. The newborns were divided into three groups: PVC group (n = 8), CPLT group (n = 4) and ventricular tachycardia group (n = 4). All patients underwent physical examination, electrocardiography, Holter monitoring and echocardiography at diagnosis and at follow-up (1, 3, 6 and 12 months, and yearly thereafter). Mean (standard deviation, SD) age of the patients was 3 (1.19) days in the PVC group, 3.25 (0.95) days in the CPLT group and 6.5 (9.1) days in the ventricular tachycardia group. Median follow-up was 36 months (range 24-48 months). PVCs disappeared during follow-up in all the neonates, in the PVC group, at a mean (SD) age of 2.1 (1.24) months; in the CPLT group, couplets disappeared at a mean (SD) age of 6.5 (1) months. All patients with ventricular tachycardia were treated; ventricular tachycardia disappeared at a mean (SD) age of 1.7 (0.9) months. Neither death nor complications occurred. Ventricular arrhythmias in newborns without heart disease have a good long-term prognosis. Frequent PVCs and CPLTs do not require treatment. Sustained ventricular tachycardia or high-rate ventricular tachycardia must be treated, but the prognosis is generally favourable.


Microwave-induced resistance oscillations and zero resistance states in 2D bilayer systems.
: We report on theoretical studies of recently obtained experimental results on microwave-induced resistance oscillations and zero resistance states in Hall bars with two occupied subbands. In these experiments, resistance presents a peculiar shape which appears to have a built-in interference effect not observed before. We apply the microwave-driven electron orbit model, which implies a radiation-driven oscillation of the two-dimensional electron system. Thus, we calculate different intra- and inter-subband electron scattering rates revealing different microwave-driven oscillations frequencies for the two electronic subbands. Calculated results are in good agreement with experiments.


Detection of t(14;18) carrying cells in bone marrow and peripheral blood from patients affected by non-lymphoid diseases.
To assess the presence of bcl-2/JH rearrangements in bone marrow and peripheral blood lymphocytes from patients affected by diseases other than malignant lymphomas. The t(14;18) (q32;q21) translocation, which juxtaposes the bcl-2 oncogene on chromosome 18 and the JH segment of the immunoglobulin heavy chain (IgH) genes on chromosome 14, is found frequently in follicular lymphomas. A sensitive semi-nested polymerase chain reaction (PCR) was used to detect t(14;18) translocation in bone marrow aspirates and peripheral blood lymphocytes from 48 patients. In 137 additional individuals peripheral blood lymphocytes only were tested. Cells carrying bcl-2/JH rearrangements were detected in about a quarter of the bone marrow samples and half of the peripheral blood lymphocyte samples. In seven patients, t(14;18) positive cells were found in both the bone marrow and peripheral blood lymphocyte samples. The size of the PCR products and bcl-2/JH DNA sequence analysis showed that the same t(14;18) carrying clone was present in the bone marrow and the corresponding peripheral blood lymphocyte samples in three of these seven patients. Some patients had more than one bcl-2/JH rearrangement. There was no significant correlation between age and the translocation incidence. Cells carrying the t(14;18) translocation were present in peripheral blood lymphocyte samples with a similar incidence--between 47% and 52% in all age groups from 20 to 79 years. Patients older than 80 years had a lower (37%) but not significantly different incidence. These findings suggest that patients affected by non-lymphoid diseases may have several t(14;18) carrying cells and some of them undergo a clonal expansion. Whether individuals with t(14;18) positive cells are at a higher risk of lymphoid malignancies remains unanswered and further epidemiological studies are required.


Characterization of the poliovirus 147S particle: new insights into poliovirus uncoating.
A Sabin 1 strain poliovirus (PV) mutant, S1(2Y-1I), carrying a Tyr at amino acid position VP2(142) and an Ile at position VP1(160), can establish persistent infections in HEp-2c cells. This mutant forms atypical 147S particles upon interaction at 0 degrees C with either cells expressing PV receptor (PVR) CD155, or PVR-IgG2a, a chimeric molecule consisting of an extracellular moiety of PVR and the hinge and Fc portion of a mouse IgG2a. Upon interaction with PVR at 37 degrees C, S1(2Y-1I), similar to the parental strain, forms both 135S A particles and 80S empty capsids. At 0 degrees C, surprisingly, at a concentration equal to or greater than 5 nM, PVR-IgG2a induced both the extrusion of VP4 from the capsid of S1(2Y-1I) and the formation of 80S particles. The same transitions were observed at 0 degrees C with the parental strain Sabin 1 at 40 nM PVR-IgG2a. Thus, the formation of 80S particles and VP4 extrusion, considered as one of the steps of PV uncoating, can be temperature-independent at high PVR concentration. This implies that structural changes of the PV capsid occurred following adsorption at low temperature.


Genetic and Pathogenicity Diversity of Aphanomyces euteiches Populations From Pea-Growing Regions in France.
Aphanomyces euteiches is an oomycete pathogen with a broad host-range on legumes that causes devastating root rot disease in many pea-growing countries and especially in France. Genetic resistance is a promising way to manage the disease since consistent QTL controlling partial resistance have been identified in near isogenic lines of pea. However, there are still no resistant pea varieties cultivated in France. This study aimed to evaluate the phenotypic and genetic diversity of A. euteiches populations from the major pea-growing regions in France. A collection of 205 isolates, from soil samples collected in infested pea fields located in five French regions, was established and genotyped using 20 SSR markers. Thirteen multilocus genotypes were found among the 205 isolates which displayed a low genotypic richness (ranged from 0 to 0.333). Two main clusters of isolates were identified using PCoA and STRUCTURE, including a predominant group comprising 88% of isolates and another group representing 12% of isolates mainly from the Bourgogne region. A subset of 34 isolates, representative of the fields sampled, was phenotyped for aggressiveness on a set of resistant and susceptible varieties of four legume hosts (pea, faba bean, vetch, alfalfa). Significant differences in disease severity were found among isolates and three groups of aggressiveness comprising 16, 17, and 2 isolates, respectively, were identified using HCA analysis. A higher diversity in pathogen aggressiveness was observed among isolates from Bourgogne, which included different legumes in its crop history. Little relationship was observed between genetic clusters and pathogenicity in the subset of 34 isolates, as expected using neutral markers. This study provides useful knowledge on the current state of low to moderate diversity among A. euteiches populations before resistant pea varieties are grown in France. New insights and hypotheses about the major factors shaping the diversity and evolution of A. euteiches are also discussed.


Efficacy of spinal manipulation/mobilization therapy. A meta-analysis.
A quantitative review (meta-analysis) was undertaken to synthesize existing evidence on the efficacy of joint mobilization and manipulation and expose consumers of rehabilitation research to the methods and procedures of quantitative reviewing. Potentially relevant studies were obtained through a computer-assisted bibliographic search of the Index Medicus data base and through examination of references contained in retrieved studies. A total of 57 titles were potentially relevant to manipulation/mobilization, but only nine met the prespecified criteria for inclusion in the quantitative review. Data analysis indicated that studies not employing random assignment were more likely to produce results supporting the use of manipulation/mobilization therapies. The effects in favor of manipulation and mobilization were greater when manual therapy was provided in conjunction with other forms of treatment and were also greater when the treatment effects were measured immediately following therapy. In addition, hypotheses tests appearing in journals published in the United States showed manipulation/mobilization less effective in comparison with reports appearing in English language journals published outside the United States. The results provided only limited empirical support for spinal mobilization and manipulation when used to treat pain, flexibility limitations, and impairment in physical activity.


Developing rice with high yield under phosphorus deficiency: Pup1 sequence to application.
The major quantitative trait locus (QTL) Phosphorus uptake1 (Pup1) confers tolerance of phosphorus deficiency in soil and is currently one of the most promising QTLs for the development of tolerant rice (Oryza sativa) varieties. To facilitate targeted introgression of Pup1 into intolerant varieties, the gene models predicted in the Pup1 region in the donor variety Kasalath were used to develop gene-based molecular markers that are evenly distributed over the fine-mapped 278-kb QTL region. To validate the gene models and optimize the markers, gene expression analyses and partial allelic sequencing were conducted. The markers were tested in more than 80 diverse rice accessions revealing three main groups with different Pup1 allele constitution. Accessions with tolerant (group I) and intolerant (group III) Pup1 alleles were distinguished from genotypes with Kasalath alleles at some of the analyzed loci (partial Pup1; group II). A germplasm survey additionally confirmed earlier data showing that Pup1 is largely absent from irrigated rice varieties but conserved in varieties and breeding lines adapted to drought-prone environments. A core set of Pup1 markers has been defined, and sequence polymorphisms suitable for single-nucleotide polymorphism marker development for high-throughput genotyping were identified. Following a marker-assisted backcrossing approach, Pup1 was introgressed into two irrigated rice varieties and three Indonesian upland varieties. First phenotypic evaluations of the introgression lines suggest that Pup1 is effective in different genetic backgrounds and environments and that it has the potential to significantly enhance grain yield under field conditions.


Some aspects of the pharmacology and physiology of the Ascaris suum muscle.
Out of 11 agonists, including such agents as bradykinin, prostaglandin E2, eledoisin, only acetylcholine (Ach) caused the isolated exposed ascaris muscle to contract during treatment for 30 sec and at 10(-7) g/ml (or lower concentrations). The possibility of using this preparation for the identification and quantification of Ach in biological tissues and fluids was highlighted. Neostigmine, but not physostigmine, augmented Ach activity. This suggests that cholinesterases present in the ascaris muscle may be structurally dissimilar to those in the mammalian gut muscle. Several chemically unrelated antagonists showed anti-Ach activity in this preparation in a descending order: d-tubocurarine (dtc) greater than mepyramine greater than atropine, decamethonium, succinylcholine greater than hexamethonium greater than piperazine. Neither adrenaline nor noradrenaline relaxed the ascaris muscle but gamma-aminobutyric acid (GABA) and, occasionally, piperazine caused immediate relaxation of the muscle. GABA was about 150 times more potent than piperazine in this regard. GABA also showed anti-Ach activity which was 0.8-3 times that of dtc. It is suggested that GABA is the inhibitory transmitter in the ascaris suum and that the anti-Ach activity of piperazine is due either to stimulation of GABA receptors and/or to nonspecific blockade of Ach receptors.


Experience of the first survey of the pilot project of Asian Quality Assurance Survey program.
The Asian Network for Clinical Laboratory Standardization (ANCLS) decided to start her First Inter-laboratory Quality Assurance survey at the business meeting during the Second Asian Colloquium on October 21-22, 2000 in Kobe, Japan. The first survey materials of Asian Quality Assurance Survey (AQuAS) were distributed in July 2001 to 21 hospitals in the field of chemistry and 22 hospitals in the field of hematology among total 24 participating laboratories from seven Asian countries: Indonesia, Japan, Korea, Malaysia, Philippines, Singapore and Thailand. The survey methods in chemistry and in hematology were somewhat different. In chemistry the survey material was considered as unknown but handled similarly to the sample from the patient. Nineteen routine tests were performed only once. The hematology samples were considered as unknown but handled similarly to control or calibration material. Five parameters were tested five times repetitively and their average for each parameter was calculated. All the results were supposed to be sent back to the office within two weeks. Although it took more than two weeks, the return rate was 100%. The analysis was performed in several ways such as all the results together, by instruments and by methods. Mean, standard deviation (SD), standard deviation index (SDI), coefficient of variation (CV) and variance index score (VIS) were to be calculated in chemistry, and in hematology the same parameter were to be calculated except CV and VIS. In the first survey, the CV in chemistry was not calculated and the analysis by instrument or by methodology was also not attempted since there were not enough participating hospitals to do such analysis. In hematology the analysis was done by instrument only. The survey process was carried out successfully though there were some difficulties in communication tools, transportation methods and handling of specimens due to different weather conditions, and returning the report in the correct unit and to the correct place. The submitted data were acceptable for analysis. There were some differences in the units of measurement in different countries or laboratories. It was necessary to convert some of the units. Some laboratories apparently do not perform certain tests such as calcium, potasium and gamma-glutamyltransferase (gamma-GT). The gamma-GT is the most frequently not performed test. With the experience of this first survey, all the members involved in the survey have been trained well to do future surveys.


Environmental conditions favoring bat infection with Histoplasma capsulatum in Mexican shelters.
Histoplasma capsulatum was isolated from gut, lung, liver, and spleen of 17 of 208 captured bats belonging to 6 different genera and species. Three of the 17 infected bats were from the State of Guerrero and 14 were from the State of Morelos. All were adult bats: 6 males (1 Pteronotus parnellii, 2 Natalus stramineus, 2 Artibeus hirsutus, and 1 Leptonycteris nivalis) and 11 females (1 Myotis californicus, 1 Mormoops megalophylla, 8 A. hirsutus, and 1 L. nivalis). High rates of bat infection with H. capsulatum were found in the monitored sites of the State of Morelos. Histoplasma infection of N. stramineus, A. hirsutus, and L. nivalis should be considered as the first records in the world. The fungus isolated from infected bats was identified by its typical mycelial-phase morphology and by its yeast-phase conversion. Exoantigen production confirmed the fungal identification by the presence of specific precipitation lines in double immunodiffusion assays using human immune serum. Histopathologic studies showed intracellular yeast-like cells compatible with H. capsulatum yeast-phase in tissues of several bats, especially in pulmonary (intra-alveolar and septal) macrophages, with none or minimal tissue reaction. In contrast to past reports, present data support a high risk of bat infection with H. capsulatum in Mexican cave environments.


TAS2R38 and its influence on smoking behavior and glucose homeostasis in the German Sorbs.
Genetic variants within the bitter taste receptor gene TAS2R38 are associated with sensitivity to bitter taste and are related to eating behavior in the Amish population. Sensitivity to bitter taste is further related to anthropometric traits in an genetically isolated Italian population. We tested whether the TAS2R38 variants (rs713598; rs1726866 and rs10246939) may be related to eating behavior, anthropometric parameters, metabolic traits and consumer goods intake in the German Sorbs. The three SNPs were genotyped in a total cohort of 1007 individuals (male/female: 405/602). The German version of the three-factor eating questionnaire was completed by 548 individuals. Genetic association analyses for smoking behavior, alcohol and coffee intake, eating behavior factors (restraint, disinhibition and hunger) and other metabolic traits were analyzed. Further, by combining the three SNPs we applied comparative haplotype analyses categorizing PAV (proline-alanine-valine) carriers (tasters) vs. homozygous AVI (alanin-valine-isoleucine) carriers (non-tasters). Significant associations of genetic variants within TAS2R38 were identified with percentage of body fat, which were driven by associations in women. In men, we observed significant associations with 30 min plasma glucose, and area under the curve for plasma glucose (0-120 min) (all adjusted P≤0.05). Further, we found that carriers of at least one PAV allele show significantly lower cigarette smoking per day (P = 0.002) as well as, albeit non-significant, lower alcohol intake. We did not confirm previously reported associations between genetic variants of TAS2R38 and eating behavior. Our data suggest that genetic variation in TAS2R38 is related to individual body composition measures and may further influence consumer goods intake in the Sorbs possibly via individual sensitivity to bitter taste.


Influence of chronic renal insufficiency on outcomes following carotid revascularization.
To examine the perioperative and long-term outcomes of patients undergoing carotid revascularization and to determine the influence moderate or severe renal insufficiency may have on these outcomes. Retrospective database review. Academic tertiary hospital. Patients undergoing carotid endarterectomy and carotid angioplasty and stenting from 1996 to 2006. Carotid revascularization. Glomerular filtration rate (GFR) was calculated based on the Modification of Diet in Renal Disease equation. Groups were analyzed by stages 0 to 2 (GFR ≥60 mL/min/1.73m(2)) vs stage 3 (GFR <60 and ≥30 mL/min/1.73m(2)) vs stages 4 and 5 (GFR <30 mL/min/1.73m(2)). Nine hundred twenty-one carotid interventions were performed (750 carotid endarterectomy, 171 carotid angioplasty and stenting). The overall 30-day mortality and morbidity rates were 1.1% and 16.9%, respectively. Sixty-six percent of patients had normal renal function (stages 0-2). Twenty-eight percent of patients had moderate renal insufficiency (stage 3) and 6% of patients had severe renal insufficiency (stages 4-5). The 30-day stroke rates for groups were 2.98% (normal renal function), 2.67% (moderate renal insufficiency), and 5.45% (severe renal insufficiency) (P = .54). Thirty-day mortality rates between groups were 0.66% (normal renal function), 1.15% (moderate renal insufficiency), and 5.45% (severe renal insufficiency) (P = .005). For carotid endarterectomy, no difference in freedom from stroke existed based on level of renal function. For carotid angioplasty and stenting, patients with severe renal insufficiency exhibited significantly lower rates of freedom from stroke. Chronic kidney disease is prevalent among patients undergoing carotid revascularization. Overall, patients with moderate renal function have similar outcomes. However, those with severe renal insufficiency have significantly higher 30-day mortality when undergoing carotid revascularization.


PEG minocycline-liposomes ameliorate CNS autoimmune disease.
Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS). Minocycline, a potent inhibitor of matrix metalloproteinase (MMP)-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG) minocycline liposomes are effective in treating EAE. Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs), we determined that PEG minocycline-liposome preparations stabilized with CaCl(2) are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number. Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.


RSK isoforms in cancer cell invasion and metastasis.
Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is the primary cause of death for patients with cancer. New therapies that prevent invasion and metastasis in combination with current treatments could therefore significantly reduce cancer recurrence and morbidity. Metastasis is driven by altered signaling pathways that induce changes in cell-cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial-to-mesenchymal transition and cell survival. The ribosomal S6 kinase (RSK) family of kinases is a group of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) effectors that can regulate these steps of metastasis by phosphorylating both nuclear and cytoplasmic targets. However, our understanding of RSK function in metastasis remains incomplete and is complicated by the fact that the four RSK isoforms perform nonredundant, sometimes opposing functions. Although some isoforms promote cell motility and invasion by altering transcription and integrin activity, others impair cell motility and invasion through effects on the actin cytoskeleton. The mechanism of RSK action depends both on the isoform and the cancer type. However, despite the variance in RSK-mediated outcomes, chemical inhibition of this group of kinases has proven effective in blocking invasion and metastasis of several solid tumors in preclinical models. RSKs are therefore a promising drug target for antimetastatic cancer treatments that could supplement and improve current therapeutic approaches. This review highlights contradiction and agreement in the current data on the function of RSK isoforms in metastasis and suggests ways forward in developing RSK inhibitors as new antimetastasis drugs.


The impact of sleep deprivation on sleepiness, risk factors and professional performance in medical residents.
Prolonged working hours and sleep deprivation can exert negative effects on professional performance and health. To assess the relationship between sleep deprivation, key metabolic markers, and professional performance in medical residents. We compared 35 residents working the in-house night shift with 35 senior year medical students in a cross-sectional cohort study. The Epworth Sleepiness Scale (ESS) questionnaire was administered and blood tests for complete blood count (CBC), blood chemistry panel, lipid profile and C-reactive protein (CRP) were obtained from all participants. Medical students and medical residents were comparable demographically except for age, weekly working hours, reported weight gain, and physical activity. The ESS questionnaires indicated a significantly higher and abnormal mean score and higher risk of falling asleep during five of eight daily activities among medical residents as compared with medical students. Medical residents had lower high density lipoprotein levels, a trend towards higher triglyceride levels and higher monocyte count than did medical students. CRP levels and other laboratory tests were normal and similar in both groups. Among the residents, 5 (15%) were involved in a car accident during residency, and 63% and 49% reported low professional performance and judgment levels after the night shift, respectively. Medical residency service was associated with increased sleepiness, deleterious lifestyle changes, poorer lipid profile, mild CBC changes, and reduced professional performance and judgment after working the night shift. However, no significant changes were observed in CRP or in blood chemistry panel. Larger prospective cohort studies are warranted to evaluate the dynamics in sleepiness and metabolic factors overtime.


Hesperidin Protects Against Intestinal Inflammation by Restoring Intestinal Barrier Function and Up-Regulating Treg Cells.
Hesperidin is an important natural phenolic compound and is considered beneficial to health. The purpose of this study is to investigate the protective effects of hesperidin on DSS-induced colitis in mice and Caco-2 cells. The DSS-induced colitis mice are assigned to 10, 20, and 40 mg kg-g hesperidin diets after DSS treatment. For in vitro experiments, Caco-2 cells are treated with TNF-α/ IFN-γ for 48 h without or with hesperidin. Hesperidin supplementation ameliorates DSS-induced colitis. Specifically, hesperidin ameliorates intestinal inflammation through decreasing MDA activity and enhancing SOD and GSH activities. Hesperidin also obviously upregulates Nrf2 antioxidant pathway and increases the protein expression of HO-1 and NQO1. Additionally, hesperidin significantly reduces the levels of inflammatory factors and increases the levels of anti-inflammatory factors in the colon tissues. Further analysis shows that hesperidin can improve the expression of tight junction proteins and intestinal permeability, as well as increases the Treg population. In Caco-2 cells, it is shown that hesperidin prevents TNF-α/IFN-γ-induced reduction in TEER and morphological disruption. Moreover, hesperidin also decreases the epithelial permeability and suppresses proinflammatory responses. Hesperidin can protect against intestinal inflammation via enhanced Nrf2 antioxidant pathway, increases the Treg population, and restores intestinal barrier function.


Sex work research: methodological and ethical challenges.
The challenges involved in the design of ethical, nonexploitative research projects with sex workers or any other marginalized population are significant. First, the size and boundaries of the population are unknown, making it extremely difficult to get a representative sample. Second, because membership in hidden populations often involves stigmatized or illegal behavior, concerns regarding privacy and confidentiality are paramount and difficult to resolve. In addition, they often result in challenges to the validity of the data. Third, in spite of evidence to the contrary, associations between sex work and victimization are still strong, dichotomies remain prevalent, and sex workers are often represented as a homogeneous population. Drawing on three research projects in which the author has been involved-all grounded in a sex-as-work approach-as well as the work of others, this article provides several strategies for overcoming these challenges. Clear guidelines for ethical, nonexploitive methodologies are embedded in the solutions provided.


Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex changes and multiple forms of chromosomal instability in colorectal cancers.
Cancers with chromosomal instability (CIN) are held to be aneuploid/polyploid with multiple large-scale gains/deletions, but the processes underlying CIN are unclear and different types of CIN might exist. We investigated colorectal cancer cell lines using array-comparative genomic hybridization (CGH) for copy number changes and single-copy number polymorphism (SNP) microarrays for allelic loss (LOH). Many array-based CGH changes were not found by LOH because they did not cause true reduction-to-homozygosity. Conversely, many regions of SNP-LOH occurred in the absence of copy number change, comprising an average per cell line of 2 chromosomes with complete LOH; 1-2 terminal regions of LOH (mitotic recombination); and 1 interstitial region of LOH. SNP-LOH detected many novel changes, representing possible locations of uncharacterized tumor suppressor loci. Microsatellite unstable (MSI+) lines infrequently showed gains/deletions or whole-chromosome LOH, but their near-diploid karyotypes concealed mitotic recombination frequencies similar to those of MSI- lines. We analyzed p53 and chromosome 18q (SMAD4) in detail, including mutation screening. Almost all MSI- lines showed LOH and/or deletion of p53 and 18q; some near-triploid lines had acquired three independent changes at these loci. We found consistent results in primary colorectal cancers. Overall, the distributions of mitotic recombination and whole-chromosome LOH in the MSI- cell lines differed significantly from random, with some lines having much higher than expected levels of these changes. Moreover, lines with more LOH changes had significantly fewer copy number changes. These data suggest that CIN is not synonymous with copy number change and some cancers have a specific tendency to whole-chromosome deletion and regain or to mitotic recombination.


Assessment of HIV molecular surveillance capacity in the European Union, 2016.
IntroductionExpanding access to HIV antiretroviral treatment is expected to decrease HIV incidence and acquired immunodeficiency syndrome (AIDS) mortality. However, this may also result in increased HIV drug resistance (DR). Better monitoring and surveillance of HIV DR is required to inform treatment regimens and maintain the long term effectiveness of antiretroviral drugs. As there is currently no formal European Union (EU)-wide collection of HIV DR data, this study aimed to assess the current HIV molecular surveillance capacity in EU/European Economic Area (EEA) countries in order to inform the planning of HIV DR monitoring at EU level. Methods: Thirty EU/EEA countries were invited to participate in a survey on HIV molecular surveillance capacity, which also included laboratory aspects. Results: Among 21 responding countries, 13 reported using HIV sequence data (subtype and/or DR) for surveillance purposes at national level. Of those, nine stated that clinical, epidemiological and sequence data were routinely linked for analysis. Discussion/conclusion: We identified similarities between existing HIV molecular surveillance systems, but also found important challenges including human resources, data ownership and legal issues that would need to be addressed.Information on capacities should allow better planning of the phased introduction of HIV DR surveillance at EU/EEA level.


Season of cancer diagnosis exerts distinct effects upon short- and long-term survival.
Several epidemiological studies have shown an association between the season in which certain cancers are diagnosed and survival, with diagnosis in summer and autumn being associated with better survival. In this study, we have added resolution to the analysis of seasonality in cancer survival by considering mortality within several nonoverlapping time periods following diagnosis, thereby quantifying the separate contributions of mechanisms operating in the short term and in the longer term. We found evidence of seasonality acting on mortality within 2 distinct periods following diagnosis. Diagnosis in the summer was associated with substantially decreased mortality within the first month of diagnosis compared with winter in men with prostate cancer, those of both sexes with colorectal or lung cancer, and most strikingly, amongst women with breast cancer (hazard ratio 0.81 [95% confidence interval 0.75-0.86]). Adjusting for monthly variations in general mortality greatly attenuated the seasonal effects on short-term mortality. At long-term follow-up (>5 years), there was a consistent shift in the seasonality pattern, with autumn diagnosis alone being associated with decreased mortality, both in female breast cancer cases and in lung cancer cases of both sexes. We conclude that the higher survival observed amongst patients diagnosed in summer and autumn is predominantly a short-term phenomenon that is largely attributable to generally higher mortality in winter. However, the distinct mortality reduction observed in the long term amongst those diagnosed in the autumn, especially amongst breast cancer patients, may indicate the presence of a seasonally variable protective mechanism.


Antioxidants vitamin C and vitamin e for the prevention and treatment of cancer.
To evaluate the evidence of the supplements vitamin C and vitamin E for treatment and prevention of cancer. Systematic review of trials and meta-analysis. DATA SOURCES AND MAIN RESULTS: Thirty-eight studies showed scant evidence that vitamin C or vitamin E beneficially affects survival. In the ATBC Cancer Prevention Study Group, no statistically significant effect of treatment was seen for any cancer individually, and our pooled relative risk (regardless of tumor type) for alpha-tocopherol alone was 0.91 (95% confidence interval [CI]: 0.74, 1.12). All cause mortality was not significant. In the Linxian General Population Trial, the relative risks for cancer death for vitamin C (combined with molybdenum) was 1.06 (95% CI: 0.92, 1.21) and for vitamin E (combined with beta-carotene and selenium) was 0.87 (95% CI: 0.76, 1.00). We identified only 3 studies that reported statistically significant beneficial results: vitamin C (in combination with BCG) was found to be beneficial in a single trial of bladder cancer and vitamin E (in combination with omega-3 fatty acid) increased survival in patients with advanced cancer. In the ATBC trial, in analyses of 6 individual cancers, the prevention of prostate cancer in subjects treated with alpha-tocopherol was statistically significant (RR=0.64, 95% CI: 0.44, 0.94). The systematic review of the literature does not support the hypothesis that the use of supplements of vitamin C or vitamin E in the doses tested helps prevent and/or treat cancer in the populations tested. There were isolated findings of benefit, which require confirmation.


Cupping for treating pain: a systematic review.
The objective of this study was to assess the evidence for or against the effectiveness of cupping as a treatment option for pain. Fourteen databases were searched. Randomized clinical trials (RCTs) testing cupping in patients with pain of any origin were considered. Trials using cupping with or without drawing blood were included, while trials comparing cupping with other treatments of unproven efficacy were excluded. Trials with cupping as concomitant treatment together with other treatments of unproven efficacy were excluded. Trials were also excluded if pain was not a central symptom of the condition. The selection of studies, data extraction and validation were performed independently by three reviewers. Seven RCTs met all the inclusion criteria. Two RCTs suggested significant pain reduction for cupping in low back pain compared with usual care (P < .01) and analgesia (P < .001). Another two RCTs also showed positive effects of cupping in cancer pain (P < .05) and trigeminal neuralgia (P < .01) compared with anticancer drugs and analgesics, respectively. Two RCTs reported favorable effects of cupping on pain in brachialgia compared with usual care (P = .03) or heat pad (P < .001). The other RCT failed to show superior effects of cupping on pain in herpes zoster compared with anti-viral medication (P = .065). Currently there are few RCTs testing the effectiveness of cupping in the management of pain. Most of the existing trials are of poor quality. Therefore, more rigorous studies are required before the effectiveness of cupping for the treatment of pain can be determined.


The role of nutrition in enhancing immunity in aging.
Aging is associated with declined immune function, particularly T cell-mediated activity, which contributes to increased morbidity and mortality from infectious disease and cancer in the elderly. Studies have shown that nutritional intervention may be a promising approach to reversing impaired immune function and diminished resistance to infection with aging. However, controversy exists concerning every nutritional regimen tested to date. In this article, we will review the progress of research in this field with a focus on nutrition factor information that is relatively abundant in the literature. While vitamin E deficiency is rare, intake above recommended levels can enhance T cell function in aged animals and humans. This effect is believed to contribute toward increased resistance to influenza infection in animals and reduced incidence of upper respiratory infection in the elderly. Zinc deficiency, common in the elderly, is linked to impaired immune function and increased risk for acquiring infection, which can be rectified by zinc supplementation. However, higher than recommended upper limits of zinc may adversely affect immune function. Probiotics are increasingly being recognized as an effective, immune-modulating nutritional factor. However, to be effective, they require an adequate supplementation period; additionally, their effects are strain-specific and among certain strains, a synergistic effect is observed. Increased intake of fish or n-3 PUFA may be beneficial to inflammatory and autoimmune disorders as well as to several age-related diseases. Conversely, the immunosuppressive effect of fish oils on T cell-mediated function has raised concerns regarding their impact on resistance to infection. Caloric restriction (CR) is shown to delay immunosenescence in animals, but this effect needs to be verified in humans. Timing for CR initiation may be important to determine whether CR is effective or even beneficial at all. Recent studies have suggested that CR, which is effective at improving the immune response of unchallenged animals, might compromise the host's defense against pathogenic infection and result in higher morbidity and mortality. The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, wholestic approach to determining the optimal nutritional strategies that would maintain a healthy immune system in the elderly and promote their resistance to infection and other immune-related diseases.


Computerized macular pathology diagnosis in spectral domain optical coherence tomography scans based on multiscale texture and shape features.
To develop an automated method to identify the normal macula and three macular pathologies (macular hole [MH], macular edema [ME], and age-related macular degeneration [AMD]) from the fovea-centered cross sections in three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) images. A sample of SD-OCT macular scans (macular cube 200 × 200 or 512 × 128 scan protocol; Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA) was obtained from healthy subjects and subjects with MH, ME, and/or AMD (dataset for development: 326 scans from 136 subjects [193 eyes], and dataset for testing: 131 scans from 37 subjects [58 eyes]). A fovea-centered cross-sectional slice for each of the SD-OCT images was encoded using spatially distributed multiscale texture and shape features. Three ophthalmologists labeled each fovea-centered slice independently, and the majority opinion for each pathology was used as the ground truth. Machine learning algorithms were used to identify the discriminative features automatically. Two-class support vector machine classifiers were trained to identify the presence of normal macula and each of the three pathologies separately. The area under the receiver operating characteristic curve (AUC) was calculated to assess the performance. The cross-validation AUC result on the development dataset was 0.976, 0.931, 0939, and 0.938, and the AUC result on the holdout testing set was 0.978, 0.969, 0.941, and 0.975, for identifying normal macula, MH, ME, and AMD, respectively. The proposed automated data-driven method successfully identified various macular pathologies (all AUC > 0.94). This method may effectively identify the discriminative features without relying on a potentially error-prone segmentation module.


Manganese, superoxide dismutase, and oxygen tolerance in some lactic acid bacteria.
A previous study of the aerotolerant bacterium Lactobacillus plantarum, which lacks superoxide dismutase (SOD), demonstrated that it possesses a novel substitute for this defensive enzyme. Thus, L. plantarum contains 20 to 25 mM Mn(II),m in a dialyzable form, which is able to scavenge O2- apparently as effectively as do the micromolar levels of SOD present in most other organisms. This report describes a survey of the lactic acid bacteria. The substitution of millimolar levels of Mn(II) for micromolar levels of SOD is a common occurrence in this group of microorganisms, which contained either SOD or high levels of Mn(II), but not both. Two strains were found which had neither high levels of Mn(II) nor SOD, and they were, as was expected, very oxygen intolerant. Lactic acid bacteria containing SOD grew better aerobically than anaerobically, whereas the organisms containing Mn(II) in place of SOD showed aerobic growth which was best, at best, equal to anaerobic growth. Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) increases the rate of O2- production in these organisms. Lactobacillus strains containing high intracellular Mn(II) were more resistant to the oxygen-dependent toxicity of plumbagin than were strains containing lower levels of Mn(II). The results support the conclusion that a high internal level of Mn(II) provides these organisms with an important defence against endogenous O2-.


Effect of Metformin and Flutamide on Anthropometric Indices and Laboratory Tests in Obese/Overweight PCOS Women under Hypocaloric Diet.
This study was designed to investigate the effect of metformin and flutamide alone or in combination with anthropometric indices and laboratory tests of obese/overweight PCOS women under hypocaloric diet. This single blind clinical trial was performed on 120 PCOS women. At the beginning, hypocaloric diet was recommended for the patients. After one month while they were on the diet, the patients were randomly divided in 4 groups; metformin (500 mg, 3/day), flutamide (250 mg, 2/day), combined, metformin (500 mg, 3/day) with flutamide (250 mg, 2/day) and finally placebo group. The patients were treated for 6 months. Anthropometric indices and laboratory tests (fasting and glucose-stimulated insulin levels, lipid profile and androgens) were measured. A one-way ANOVA (Post Hoc) and paired t-test were performed to analyze data. A p ≤ 0.05 was considered statistically significant. After treatment, reduction in weight, BMI, hip circumference was significantly greater in the metformin group in comparison to other groups (p<0.05). In addition, the fasting insulin was significantly greater in metformin group and flutamide group in comparison to metformin+flutamide and placebo groups after treatment (p<0.05). Within groups, insulin level showed significant changes (before and after treatment) in metformin+flutamide group and LDL reduction was significant in flutamide group before and after treatment. Post hoc tukey and two-tailed with p≤0.05 were used to define statistical significance. Using combination of metformin and flutamide improves anthropometric indices and laboratory tests in obese/overweight PCOS women under hypocaloric diet.


Randomised controlled trial of training health visitors to identify and help couples with relationship problems following a birth.
Stresses imposed by parenthood can provoke or intensify relationship problems between parents. These problems, which are often associated with postnatal depression, can have serious consequences for family well-being but are often not revealed to primary health care personnel. To evaluate a means of extending the primary health care team's ability to identify and respond to relationship problems of mothers and their partners in the postnatal period. Cluster randomised controlled trial. Specially trained health visitors in nine 'intervention' clinics--each matched with a 'control' clinic' in an outer London borough. Health visitors in intervention clinics invited mothers attending for the six-to-eight-week developmental check to complete a screening scale for relationship problems, and offered help (supportive listening, advice, or referral) if needed. When visiting the clinic for the 12-week immunizations, mothers from all clinics were asked to complete a follow-up self-report questionnaire. After the completion of the trial, 25 women who had attended the intervention clinics and had been offered support with a relationship problem were interviewed to elicit their views on the acceptability and value of the intervention. All 25 of the health visitors engaged in the intervention were asked to complete a questionnaire on their experience. Screening led to striking differences between intervention and control clinics in the percentage of women identified at the six-to-eight-week check as potentially in need of help with a relationship problem (21% versus 5%, P = 0.007) and in the percentage actually offered help (18% versus 3%, P = 0.014). About one-half of the mothers so identified were also identified as having postnatal depression. At the 12-week visit for immunizations, the intervention group was twice as likely (P = 0.006) as the control group to report having discussed relationship problems with the health visitor and 75% more likely (P = 0.046) to report having received help with a problem. The intervention offers a useful way of extending the primary health care team's ability to respond to problems that often have serious consequences for family well-being.


Cognitive behavioral therapy for insomnia outcomes in women after primary breast cancer treatment: a randomized, controlled trial.
To examine the effect of cognitive-behavioral therapy for insomnia (CBTI) on sleep improvement, daytime symptoms, and quality of life (QOL) in breast cancer survivors (BCSs) after cancer treatment. A prospective, longitudinal, randomized, controlled trial. Oncology clinics, breast cancer support groups, and communities in Colorado. 56 middle-aged BCSs with chronic insomnia. Women were randomly assigned to CBTI or behavioral placebo treatment (BPT) and completed measures of sleep, QOL, functioning, fatigue, and mood at baseline, postintervention, and at three- and six-month follow-ups. Sleep outcomes (e.g., sleep efficiency, sleep latency, total sleep time, wake after sleep onset, number of nightly awakenings); secondary variables included sleep medication use, insomnia severity, QOL, physical function, cognitive function, fatigue, depression, anxiety, and sleep attitudes or knowledge. Sleep efficiency and latency improved more in the CBTI group than the BPT group; this difference was maintained during follow-up. Women in the CBTI group had less subjective insomnia, greater improvements in physical and cognitive functioning, positive sleep attitudes, and increased sleep hygiene knowledge. No group differences in improvement were noted relative to QOL, fatigue, or mood. Nurse-delivered CBTI appears to be beneficial for BCSs' sleep latency/efficiency, insomnia severity, functioning, sleep knowledge, and attitudes more than active placebo, with sustained benefit over time. Oncology nurses are in a unique position to identify insomnia in cancer survivors. When sleep disturbances become chronic, nurses need to make recommendations and referrals.


Runners adjust leg stiffness for their first step on a new running surface.
Human runners adjust the stiffness of their stance leg to accommodate surface stiffness during steady state running. This adjustment allows runners to maintain similar center of mass movement (e.g., ground contact time and stride frequency) regardless of surface stiffness. When runners encounter abrupt transitions in the running surface, they must either make a rapid adjustment or allow the change in the surface stiffness to disrupt their running mechanics. Our goal was to determine how quickly runners adjust leg stiffness when they encounter an abrupt but expected change in surface stiffness that they have encountered previously. Six human subjects ran at 3 m s(-1) on a rubber track with two types of rubber surfaces: a compliant "soft" surface (ksurf = 21.3 kN m(-1) and a non-compliant "hard" surface (ksurf = 533 kN m(-1). We found that runners completely adjusted leg stiffness for their first step on the new surface after the transition. For example, runners decreased leg stiffness by 29% between the last step on the soft surface and the first step on the hard surface (from 10.7 kN m(-1) to 7.6 kN m(-1), respectively). As a result, the vertical displacement of the center of mass during stance ( approximately 7 cm) did not change at the transition despite a reduction in surface compression from 6 cm to less than 0.25 cm. By rapidly adjusting leg stiffness, each runner made a smooth transition between surfaces so that the path of the center of mass was unaffected by the change in surface stiffness.


Chronic Giardia muris infection in anti-IgM-treated mice. I. Analysis of immunoglobulin and parasite-specific antibody in normal and immunoglobulin-deficient animals.
To investigate the role of B cells and antibody in the immune response of mice to the murine intestinal parasite Giardia muris, we used mice treated from birth with rabbit anti-IgM antisera (aIgM). Such mice developed in serum and in gut secretions extreme Ig deficiency (IgM, IgA, and IgG) relative to control animals. The aIgM-treated mice showed no anti-G. muris antibody in serum or in gut wash material. Infections of G. muris in these mice were chronic, with a high load of parasite present in the small bowel, as reflected by prolonged cyst excretion (greater than 11 wk) and high trophozoite counts. In contrast, normal, untreated mice or NRS-treated animals developed anti-parasite IgA and IgG antibody in serum, demonstrated IgA antibody against the parasite in gut washings, and expelled the parasite within 9 wk. These effects of aIgM treatment on the murine response to primary infection with G. muris were demonstrated in two strains of mice: BALB/c and (C57BL/6 X C3H/He) F1. It was also observed that the response to G. muris infection in untreated animals was characterized by higher than normal total secretion of IgA into the gut and a concomitant increase in the serum polymeric IgA level. Mice treated with aIgM had a marked decrease of both monomeric and polymeric IgA in serum, and little detectable IgA in the intestinal lumen. These experiments provide the first demonstration that anti-IgM treatment suppresses a specific intestinal antibody response to antigen, and provide evidence that B cells and antibody play a role in the development of an effective response to a primary infection with G. muris in mice.


Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder.
This study explored whether cerebral metabolic changes seen in treatment resistant and rapid cycling bipolar depression inpatients are also found in an outpatient sample not specifically selected for treatment resistance or rapid cycling. We assessed 15 depressed outpatients with bipolar disorder (six type I and nine type II) who were medication-free for at least 2 weeks and were not predominantly rapid cycling. The average 28-item Hamilton Depression Scale (HAM-D) total score was 33.9. The healthy control group comprised 19 age-matched subjects. All participants received a resting quantitative 18F-fluoro-deoxyglucose positron emission tomography scan. Data analyses were performed with Statistical Parametric Mapping (SPM5). Analyses revealed that depressed patients exhibited similar global metabolism, but decreased absolute regional metabolism in the left much more than right dorsolateral prefrontal cortex, bilateral (left greater than right) insula, bilateral subgenual prefrontal cortex, anterior cingulate, medial prefrontal cortex, ventral striatum, and right precuneus. No region exhibited absolute hypermetabolism. Moreover, HAM-D scores inversely correlated with absolute global metabolism and regional metabolism in the bilateral medial prefrontal gyrus, postcentral gyrus, and middle temporal gyrus. Analysis of relative cerebral metabolism yielded a similar, but less robust pattern of findings. Our findings confirm prefrontal and anterior paralimbic metabolic decreases in cerebral metabolism outside of inpatients specifically selected for treatment resistant and rapid cycling bipolar disorder. Prefrontal metabolic rates were inversely related to severity of depression. There was no evidence of regional hypermetabolism, perhaps because this phenomenon is less robust or more variable than prefrontal hypometabolism.


Inflammatory and immunological responses to hyaluronan preparations. Study of a murine biocompatibility model.
Intra-articular injection of hyaluronan preparations is a popular treatment for osteoarthritis of the knee. Recently, clinical reports have described acute inflammatory reactions in joints following these injections. The purpose of this study was to use a murine pouch model to study the local inflammatory and possibly immunological effects of three commercially available hyaluronan-derived products. Each of three different hyaluronan products (Synvisc, Hyalgan, and Supartz) was injected into air pouches established in groups of BALB/c mice. A positive control group (with particle-induced inflammation) and a negative control group (injected with saline solution) were also included. After fourteen days, the mice were killed and the air pouches were explanted and prepared for histological evaluation of the local inflammatory reaction. The antibody response was measured with use of ELISA (enzyme-linked immunosorbent assay) of serum samples obtained after the mice were killed. Histological analysis revealed a significant increase in total membrane cellularity (p < 0.001 to p < 0.03) after the use of all hyaluronan preparations. The increased cellularity was attributed to an inflammatory cell influx, rather than accumulation of fibroblasts, and elevated lymphocyte counts were observed in membranes stimulated by Synvisc (hylan G-F 20). The ELISA data revealed an antibody response to the Synvisc preparation. This immunological response was directed against a non-hyaluronan portion of the product, as indicated by the lack of cross-reactivity with the other hyaluronan products. These findings demonstrate that all three hyaluronan preparations, as currently manufactured, can cause an inflammatory soft-tissue reaction, but only the non-hyaluronan portion of the Synvisc product created an immunological response. It appears likely that this component may be the target of adverse responses in patients.


Determinants of Aortic Root Dilatation and Reference Values Among Young Adults Over a 20-Year Period: Coronary Artery Risk Development in Young Adults Study.
Aortic size increases with age, but factors related to such dilatation in healthy young adult population have not been studied. We aim to evaluate changes in aortic dimensions and its principal correlates among young adults over a 20-year time period. Reference values for aortic dimensions in young adults by echocardiography are also provided. Healthy Coronary Artery Risk Development in Young Adults (CARDIA) study participants aged 23 to 35 years in 1990-1991 (n=3051) were included after excluding 18 individuals with significant valvular dysfunction. Aortic root diameter (ARD) by M-mode echocardiography at year-5 (43.7% men; age, 30.2 ± 3.6 years) and year-25 CARDIA exams was obtained. Univariable and multivariable analyses were performed to assess associations of ARD with clinical data at years-5 and -25. ARD from year-5 was used to establish reference values of ARD in healthy young adults. ARD at year-25 was greater in men (33.3 ± 3.7 versus 28.7 ± 3.4 mm; P<0.001) and in whites (30.9 ± 4.3 versus 30.5 ± 4.1 mm; P=0.006). On multivariable analysis, ARD at year-25 was positively correlated with male sex, white ethnicity, age, height, weight, 20-year gain in weight, active smoking at baseline, and 20-year increase in diastolic, systolic, and mean arterial pressure. A figure showing the estimated 95th percentile of ARD by age and body surface area stratified by race and sex is provided. This study demonstrates that smoking, blood pressure, and increase in body weight are the main modifiable correlates of aortic root dilation during young adulthood. Our study also provides reference values for ARD in young adults.


Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.
Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma.


Implications for environmental health of multiple stressors.
Recent insights into the mechanisms underlying the biological effects of low dose effects of ionising radiation have revealed that similar mechanisms can be induced by chemical stressors in the environment. This means that interactions between radiation and chemicals are likely and that the outcomes following mixed exposures to radiation and chemicals may not be predictable for human health, by consideration of single agent effects. Our understanding of the biological effects of low dose exposure has undergone a major paradigm shift. We now possess technologies which can detect very subtle changes in cells due to small exposures to radiation or other pollutants. We also understand much more now about cell communication, systems biology and the need to consider effects of low dose exposure at different hierarchical levels of organisation from molecules up to and including ecosystems. Furthermore we understand, at least in part, some of the mechanisms which drive low dose effects and which perpetuate these not only in the exposed organism but also in its progeny and in certain cases, its kin. This means that previously held views about safe doses or lack of harmful effects cannot be sustained. The International Commission on Radiological Protection (ICRP) and all national radiation and environmental protection organisations have always accepted a theoretical risk and have applied the precautionary principle and the LNT (linear-non-threshold) model which basically says that there is no safe dose of radiation. Therefore even in the absence of visible effects, exposure of people to radiation is strictly limited. This review will consider the historical context and the new discoveries and will focus on evidence for emergent effects after mixed exposures to combined stressors which include ionising radiation. The implications for regulation of low dose exposures to protect human health and environmental security will be discussed.


Practices of Depression Care in Home Health Care: Home Health Clinician Perspectives.
The study assessed gaps between published best practices and real-world practices of treating depression in home health care (HHC) and barriers to closing gaps. The qualitative study used semistructured interviews with nurses and administrators (N=20) from five HHC agencies in five states. Audio-recorded interviews were transcribed and analyzed by a multidisciplinary team using grounded theory method to identify themes. Routine HHC nursing overlapped with all functional areas of depression care. However, gaps were noted between best and real-world practices. Gaps were associated with perceived scope of practice by HHC nurses, knowledge gaps and low self-efficacy in depression treatment, stigma attached to depression, poor quality of antidepressant management in primary care, and poor communication between HHC and primary care clinicians. Strategies to close gaps between typical and best practices include enhancing HHC clinicians' knowledge and self-efficacy with depression treatment and improving the quality of antidepressant management and communication with primary care.


Disentangling autism spectrum and attention-deficit/hyperactivity symptoms over development in fragile X syndrome.
Even genetic disorders associated with monogenic aetiologies are characterized by complex and variable risk for poor outcomes, highlighting the need to follow trajectories longitudinally. Here, we investigated the longitudinal relationships between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) symptoms in a population at high risk for both: boys with fragile X syndrome. 59 boys with fragile X syndrome aged 3-10 years old at entry participated in this study, and were followed up one and two years after their first visit. As expected, we found strong relationships over three timepoints for ADHD symptoms (as measured by the parent-rated Conners scale) and ASD symptoms (as measured by the Social Communication Questionnaire [SCQ]). In addition, using structural equation modeling (SEM) we found that ADHD symptoms at time 2 predicted ASD symptoms at time 3, suggestive of a causal relationship. Importantly, these relationships hold when including chronological age at entry to the study, as well as when including severity of impairment as measured by IQ, and their effects on both ASD and ADHD symptoms do not reach significance. This result highlights the need to study outcomes longitudinally and it informs the comorbidity of the two symptom domains in FXS as well as their potential directionality, both of which have been little researched. In addition, our findings may suggest a future need to study how ADHD symptoms and their treatment impact individuals with ASD.


Combined CT coronary angiography and stress myocardial perfusion imaging for hemodynamically significant stenoses in patients with suspected coronary artery disease: a comparison with fractional flow reserve.
We sought to determine the accuracy of combined coronary computed tomography angiography (CTA) and computed tomography stress myocardial perfusion imaging (CTP) in the detection of hemodynamically significant stenoses using fractional flow reserve (FFR) as a reference standard in patients with suspected coronary artery disease. CTP can be qualitatively assessed by visual interpretation or quantified by the transmural perfusion ratio determined as the ratio of subendocardial to subepicardial contrast attenuation. The incremental value of each technique in addition to coronary CTA to detect hemodynamically significant stenoses is not known. Forty symptomatic patients underwent FFR and 320-detector computed tomography assessment including coronary CTA and CTP. Myocardial perfusion was assessed using the transmural perfusion ratio and visual perfusion assessment. Computed tomography images were assessed by consensus of 2 observers. Transmural perfusion ratio <0.99 was used as the threshold for abnormal perfusion. FFR ≤0.8 indicated hemodynamically significant stenoses. Coronary CTA detected FFR-significant stenoses with 95% sensitivity and 78% specificity. The additional use of visual perfusion assessment and the transmural perfusion ratio both increased the specificity to 95%, with sensitivity of 87% and 71%, respectively. The area under the receiver-operating characteristic curve for coronary CTA + visual perfusion assessment was significantly higher than both coronary CTA (0.93 vs. 0.85, p = 0.0003) and coronary CTA + the transmural perfusion ratio (0.93 vs. 0.79, p = 0.0003). Per-vessel and per-patient accuracy for coronary CTA, coronary CTA + the transmural perfusion ratio, and coronary CTA + visual perfusion assessment was 83% and 83%, 87% and 92%, and 92% and 95%, respectively. In suspected coronary artery disease, combined coronary CTA + CTP identifies patients with hemodynamically significant stenoses with >90% accuracy compared with FFR. When interpreted with coronary CTA, visual perfusion assessment provided superior incremental value in the detection of FFR-significant stenoses compared with the quantitative transmural perfusion ratio assessment.


Non-cancer, cancer, and dermal sensitization risk assessment of heavy metals in cosmetics.
The heavy metal content of cosmetics may be a cause for concern in that exposure to these metals is associated with adverse consequences. Thus, the aim of this study was to assess consequences attributed to exposure to heavy metals in cosmetics as determined by non-cancer, cancer, and sensitization risks methodologies. The quantification and exposure assessments of aluminum (Al), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), lead (Pb), mercury (Hg), cadmium (Cd), antimony (Sb), and titanium (Ti) were performed by inductively coupled plasma-mass spectrometry. The non-cancer risk assessment of Al, Cr3+, Mn, Fe, Co, Ni, Cu, Zn, Cd, Sb, and Ti in cosmetic samples resulted in a margin of safety (MOS) greater than 100 or a hazard index (HI) of less than 1. However, the probability of lifetime cancer risk (LCR) resulting from dermal exposure to heavy metals from cosmetics exceeded the acceptable risk levels (LCR > 10-5). An exposure-based sensitization quantitative risk assessment determined that the ratios of acceptable exposure level to consumers for Ni, Co, Cu, or Hg were above 1, suggesting an absence of skin-sensitizing potential. For an average daily user of lip cosmetics, the estimated intakes of heavy metals were within the acceptable daily intake (ADI). The percentage of heavy users for which metal intakes exceeded ADIs were 20.37% for Pb, 9.26% for Mn, 1.85% for Cr3+, and 1.85% for Cr6+, respectively. Data suggested that the heavy metals present in cosmetics do not appear to pose a serious risk to health. However, for heavy users of lip cosmetics, contamination with some heavy metals, such as Pb, Mn, and Cr needs to be minimized.


Suppression of undesired diffraction orders of binary phase holograms.
A method to remove undesired diffraction orders of computer-generated binary phase holograms is demonstrated. Normally, the reconstruction of binary Fourier holograms, made from just two phase levels, results in an undesired inverted image from the minus first diffraction order, which is superposed with the desired one. This can be avoided by reconstructing the hologram with a diffuse light field with a pseudorandom, but known, phase distribution, which is taken into account for the hologram computation. As a consequence, only the desired image is reconstructed, whereas all residual light is dispersed, propagating as a diffuse background wave. The method may be advantageous to employ ferroelectric spatial light modulators as holographic display devices, which can display only binary phase holograms, but which have the advantage of fast switching rates.


Ultrasound-Mediated Self-Healing Hydrogels Based on Tunable Metal-Organic Bonding.
Stimulus-responsive hydrogels make up an important class of programmable materials for a wide range of biomedical applications. Ultrasound (US) is a stimulus that offers utility because of its ability to permeate tissue and rapidly induce chemical alterations in aqueous media. Here we report on the synthesis and US-mediated disintegration of stimulus-responsive telechelic Dopa-modified polyethylene glycol-based hydrogels. Fe3+-[PEG-Dopa]4 hydrogels are formed through Fe3+-induced cross-linking of four-arm polyethylene glycol-dopamine precursors to produce networks. The relative amounts of H-bonds, coordination bonds, and covalent bonds can be controlled by the [Fe3+]:[Dopa] molar ratio in precursor solutions. Networks formed from precursors with high [Fe3+]:[Dopa] ratios create mechanically robust networks (G' = 6880 ± 240 Pa) that are largely impervious to US-mediated disintegration at intensities of ≤43 W/cm2. Conversely, lightly cross-linked networks formed through [Fe3+]:[Dopa] molar ratios of <0.73 are susceptible to rapid disintegration upon exposure to US. Pulsatile US exposure allows temporal control over hydrogel disintegration and programmable self-healing. Sustained US energy can also stabilize hydrogels through the formation of additional cross-links via free radical-mediated coupling of pendant catechols. Taken together, the diverse ranges of mechanical behavior, self-healing capability, and differential susceptibility to ultrasonic disintegration suggest that Fe3+-[PEG-Dopa]4 hydrogels yield a class of application-specific stimulus-responsive polymers as smart materials for applications ranging from transient medical implants to matrices for smart drug delivery.


The shape of beauty: determinants of female physical attractiveness.
Rarely has one research area gained as much attention as that which is observed for female physical attractiveness. The past decade has resulted in numerous, exciting developments, particularly with respect to three proposed determinants of beauty: waist to hip ratio (WHR), body mass index (BMI), and curvaceousness. The goal of our paper is to provide a highly necessary review of contemporary research on the female attractiveness, including an in-depth examination of these factors. In our review, we first discuss WHR, an index of fat deposition, which is calculated by measuring the circumference of the waist compared to the circumference of the hips. WHR is controlled by the sex hormones, and increases as women age, and hence, may influence perceptions of attractiveness. This factor has been hotly contested, as some researchers have claimed that a WHR of approximately 0.7 is universally most attractive, whereas others have found inconsistent findings, or suggest the importance of other factors, such as BMI. Body mass index (BMI), calculated by dividing the body weight (in kilograms) by height (in meters) squared, serves as a measure of body fat. Although WHR and BMI are correlated, they lead to different conclusions, and the importance of BMI as a measure of female attractiveness is debated in the literature. Similar to WHR research, BMI and its role in attractiveness is not cross-culturally consistent and is affected by the availability of resources within a given environment. It may be the case that both WHR and BMI influence female attractiveness. However, there has been little investigation of this possibility. We have explored this issue in our research, which revealed that both influence attractiveness, but in addition, we noticed that curvaceousness was also a factor. Curvaceousness is the degree of "hourglass" shape as determined, for example, by the size of the bust, relative to the circumference of the hips and waist, and the size of the buttocks. However, curvaceousness does not appear to be temporally stable as a marker of attractiveness, and it is not consistent across modes of presentation. For example, models in male-oriented magazines are more curvaceous than models in female-oriented magazines. In summary, faced with these recent findings, it is difficult to ascertain agreement among the various factors, especially when researchers investigate each determinant in isolation. We conclude that, although researchers have made many important initial steps in examining female attractiveness, there remains much to be discovered.


A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation.
The purpose of this study was to identify significant, independent factors that predicted 6 month patient and graft survival after pediatric liver transplantation. The Studies of Pediatric Liver Transplantation (SPLIT) is a multicenter database established in 1995, of currently more than 4000 US and Canadian children undergoing liver transplantation. Previous published analyses from this data have examined specific factors influencing outcome. This study analyzes a comprehensive range of factors that may influence outcome from the time of listing through the peri- and postoperative period. A total of 42 pre-, peri- and posttransplant variables evaluated in 2982 pediatric recipients of a first liver transplant registered in SPLIT significant at the univariate level were included in multivariate models. In the final model combining all baseline and posttransplant events, posttransplant complications had the highest relative risk of death or graft loss. Reoperation for any cause increased the risk for both patient and graft loss by 11 fold and reoperation exclusive of specific complications by 4 fold. Vascular thromboses, bowel perforation, septicemia, and retransplantation, each independently increased the risk of patient and graft loss by 3 to 4 fold. The only baseline factor with a similarly high relative risk for patient and graft loss was recipient in the intensive care unit (ICU) intubated at transplant. A significant center effect was also found but did not change the impact of the highly significant factors already identified. We conclude that the most significant factors predicting patient and graft loss at 6 months in children listed for transplant are posttransplant surgical complications.


Uptake and Acceptability of Oral HIV Self-Testing among Community Pharmacy Clients in Kenya: A Feasibility Study.
While HIV testing and counselling is a key entry point for treatment as prevention, over half of HIV-infected adults in Kenya are unaware they are infected. Offering HIV self-testing (HST) at community pharmacies may enhance detection of undiagnosed infections. We assessed the feasibility of pharmacy-based HST in Coastal Kenya. Staff at five pharmacies, supported by on-site research assistants, recruited adult clients (≥18 years) seeking services indicative of HIV risk. Participants were offered oral HST kits (OraQuick®) at US$1 per test. Within one week of buying a test, participants were contacted for post-test data collection and counselling. The primary outcome was test uptake, defined as the proportion of invited clients who bought tests. Views of participating pharmacy staff were solicited in feedback sessions during and after the study. Between November 2015 and April 2016, 463 clients were invited to participate; 174 (38%) were enrolled; and 161 (35% [95% Confidence Interval (CI) 31-39%]) bought a test. Uptake was higher among clients seeking HIV testing compared to those seeking other services (84% vs. 11%, adjusted risk ratio 6.9 [95% CI 4.9-9.8]). Only 4% of non-testers (11/302) stated inability to pay as the reason they did not take up the test. All but one tester reported the process was easy (29%) or very easy (70%). Demand for HST kits persisted after the study and participating service providers expressed interest in continuing to offer the service. Pharmacy HST is feasible in Kenya and may be in high demand. The uptake pattern observed suggests that a client-initiated approach is more feasible compared to pharmacy-initiated testing. Price is unlikely to be a barrier if set at about US$1 per test. Further implementation research is required to assess uptake, yield, and linkage to care on a larger scale.


Geographical variations in sex ratio trends over time in multiple sclerosis.
A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out. In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas. Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births. Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS. Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.


"Looks Can Be Deceiving": Adrenal Teratoma Causing Diagnostic Difficulty.
Teratomas are unusual tumours that derived from totipotent cells with their origin from more than one or usually all three germ cells. Here authors are presenting a case of primary retroperitoneal tumour that is a rare clinical entity. A 19-year-old male presented with right lumbar pain and was found to have complex cyst with large calcification in right adrenal gland on imaging. Intraoperatively, he was found to have a solid mass with areas of soft consistency, which was excised en bloc. On gross examination, the cyst contained pieces of bone, few teeth, and hairs entangled in mucinous material. On histological evaluation, it was confirmed to be mature teratoma arising from the right adrenal gland. He made uneventful recovery and was kept well on annual follow-up.


A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome.
To test the efficacy of a proprietary nutraceutical combination in reducing insulin resistance associated with the metabolic syndrome (MetS). Sixty-four patients with MetS followed at a tertiary outpatient clinic were randomly assigned to receive either placebo or a proprietary nutraceutical combination (AP) consisting of berberine, policosanol and red yeast rice, in a prospective, double-blind, placebo-controlled study. Evaluations were performed at baseline and after 18 wk of treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) index was the primary outcome measure. Secondary endpoints included lipid panel, blood glucose and insulin fasting, after a standard mixed meal and after an oral glucose tolerance test (OGTT), flow-mediated dilation (FMD), and waist circumference. Fifty nine patients completed the study, 2 withdrew because of adverse effects. After 18 wk there was a significant reduction in the HOMA-IR index in the AP group compared with placebo (ΔHOMA respectively -0.6 ± 1.2 vs 0.4 ± 1.9; P < 0.05). Total and low density lipoprotein cholesterol also significantly decreased in the treatment arm compared with placebo (Δlow density lipoprotein cholesterol -0.82 ± 0.68 vs -0.13 ± 0.55 mmol/L; P < 0.001), while triglycerides, high density lipoprotein cholesterol, and the OGTT were not affected. In addition, there were significant reductions in blood glucose and insulin after the standard mixed meal, as well as an increase in FMD (ΔFMD 1.9 ± 4.2 vs 0 ± 1.9 %; P < 0.05) and a significant reduction in arterial systolic blood pressure in the AP arm. This short-term study shows that AP has relevant beneficial effects on insulin resistance and many other components of MetS.


Using EMR data to evaluate a physician-developed lifestyle plan for obese patients in primary care.
To use primary care electronic medical records (EMRs) to evaluate the effects of a lifestyle intervention delivered to obese patients compared with obese patients who did not receive the intervention. Retrospective cohort analysis using EMR data derived from the Canadian Primary Care Sentinel Surveillance Network. A primary care clinic in rural Alberta. Obese adult patients with at least 1 weight measurement in the time periods before and after the intervention, grouped by patients who received the intervention (n = 68) and those who did not (n = 365). Physician-developed lifestyle plan to address obesity through a variety of health-promoting recommendations. Mean change from before the intervention for weight, blood pressure, glycated hemoglobin A1c level, and body mass index measurements, compared between the control and intervention groups. Negligible weight change was observed in both groups, with the exception of older male patients (65 years and older) receiving the intervention, who lost significantly more weight than older men in the control group (a difference in mean reduction of 3.02 kg in favour of the intervention; P = .008). No overall group differences were seen in the secondary health outcomes, except for reductions in systolic and diastolic blood pressures in the intervention group (P = .002 and P = .04, respectively). Only the difference in systolic blood pressure remained significant after adjusting for covariates (P = .01). Providing real-time feedback about clinical interventions is possible using EMR data. Although the lifestyle intervention was associated with significant weight loss for a specific group of patients only, with the use of EMR data the cohort can be followed over time and additional health outcomes can be monitored. There is potential for individual physicians and practices to assess and improve clinical processes and interventions in a rigorous, timely, and manageable way.


Rapid and cytocompatible cell-laden silk hydrogel formation via riboflavin-mediated crosslinking.
Bioactive hydrogels based on naturally-derived polymers are of great interest for regenerative medicine applications. Among naturally-derived polymers, silk fibroin has been extensively explored as a biomaterial for tissue engineering due to its unique mechanical properties. Here, we demonstrate the rapid gelation of cell-laden silk fibroin hydrogels by visible light-induced crosslinking using riboflavin as a photo-initiator, in presence of an electron acceptor. The gelation kinetics were monitored by in situ photo-rheometry. Gelation was achieved in minutes and could be tuned owing to its direct proportionality to the electron acceptor concentration. The concentration of the electron acceptor did not affect the elastic modulus of the hydrogels, which could be altered by varying the polymer content. Further, the biocompatible riboflavin photo-initiator combined with sodium persulfate allowed for the encapsulation of cells within silk fibroin hydrogels. To confirm the cytocompatibility of the silk fibroin formulations, three cell types (articular cartilage-derived progenitor cells, mesenchymal stem cells and dental-pulp-derived stem cells) were encapsulated within the hydrogels, which associated with a viability >80% for all cell types. These results demonstrated that fast gelation of silk fibroin can be achieved by combining it with riboflavin and electron acceptors, which results in a hydrogel that can be used in tissue engineering and cell delivery applications.


Distinguishing between gaming and gambling activities in addiction research.
Gambling and gaming activities have become increasingly recognised as sharing many common features at a structural and aesthetic level. Both have also been implicated as contributing to harm through excessive involvement. Despite this, relatively little attention has been given to the fundamental characteristics that differentiate these two classes of activity, especially in situations where the boundaries between them may be particularly hard to distinguish. This is evident, for example, in digital games that incorporate free and paid virtual currencies or items, as well as the capacity for wagering. Such overlaps create problems for regulatory classifications, screening, diagnosis and treatment. Is the problem related to the gambling or gaming content? In this paper, we review the principal sources of overlap between the activity classes in terms of several dimensions: interactivity, monetisation, betting and wagering, types of outcomes, structural fidelity, context and centrality of content, and advertising. We argue that gaming is principally defined by its interactivity, skill-based play, and contextual indicators of progression and success. In contrast, gambling is defined by betting and wagering mechanics, predominantly chance-determined outcomes, and monetisation features that involve risk and payout to the player. A checklist measure is provided, with practical examples, to examine activities according to features of design and function, which may inform guidelines for policy makers, researchers and treatment providers. We suggest that, in some instances, using category-based nomenclature (e.g., "gambling-like game") may be too vague or cumbersome to adequately organise our understanding of new gaming/gambling hybrid activities.


The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study.
Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score > or = 18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.